Atrial fibrillation (AF) is the most prevalent arrhythmia, the incidence of which increases with age. It is estimated that 8% of all people over the age of 80 experience this type of abnormal heart rhythm and AF accounts for one-third of hospital admissions for cardiac rhythm disturbances. Over 2.2 million people are believed to have AF in the United States alone (Fuster, et al. Circulation 2006 114: e257-354). Although atrial fibrillation is often asymptomatic it may cause palpitations or chest pain. Prolonged atrial fibrillation often results in the development of congestive heart failure and/or stroke. Heart failure develops as the heart attempts to compensate for the reduced cardiac efficiency while stroke may occur when thrombi form in the atria, pass into the blood stream and lodge in the brain. Pulmonary emboli may also develop in this manner.
Calmodulin-dependent protein kinase II (CaMKII) enzymes transmit calcium ion (Ca2+) signals released inside the cell by regulating signal transduction pathways through phosphorylation. There are four isoforms of CaMKII: α, β, γ and δ, with CaMKIIδ as the predominant isoform expressed in the heart. When calcium ions bind to CaM, the resulting activated Ca2+/CaM complex phosphorylates other proteins within the cell. Specifically, activated CaMKIIδ phosphorylates a number of key Ca2+ handling proteins in cardiac myocytes, including ryanodine receptor 2 (RyR2), phospholamban (PLB), the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and the L-type Ca2+ channel (LTCC).
An increase in Ca2+/CaMKII activity has been implicated as a contributory cause of cardiac arrhythmias, diastolic heart failure (Ai, et al. Circ. Res. 2005, 97:1314-22) and in the induction and maintenance of atrial fibrillation (Dobrev, et al., Trends Cardiovasc Med., 2010, 20(1), 30-4). Thus, there is a need to discover CAMKII inhibitors for the treatment of cardiac diseases including atrial fibrillation and heart failure.